The present invention relates generally to a method for controlling fertility and/or modulating the maintenance of pregnancy in animals. The present invention further provides an animal model useful for screening for therapeutic agents to treat infertility, to prevent or reduce spontaneous abortion and/or as contraceptive agents in animals.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID Nos.) for the nucleotide and amino acid sequences referred to in the specification are defined following the bibliography.
The increasing sophistication of recombinant DNA technology is greatly facilitating research and development in the medical and allied health fields. A particularly important area of research involves cytokines and growth factors and their putative roles in fertility, birth control and pregnancy maintenance in humans and animals.
Approximately one third of normal human pregnancies end in spontaneous abortion and about one fifth of these during the very early stages of pregnancy. In the animal and livestock industry, spontaneous abortion is a major economic consideration. There is a need, therefore, to further investigate the basis behind spontaneous abortion and to develop appropriate therapeutic means for reducing its occurrence. There is also a need to investigate ways of improving the fertility rates of animals and to treat infertility in males and females. In work leading up to the present invention, the inventors investigated the role of IL-11 in fertility and pregnancy.
Interleukin(IL)-11 (IL-11) is a cytokine with many biological actions (1). It was originally cloned based on its ability to stimulate proliferation of a murine IL-6 dependent plasmacytoma cell line (2) and to inhibit adipogenesis (3). Within the hematopoietic system, IL-11 actions include stimulation of multipotential progenitors (4) and effects on erythropoiesis (5), megakaryopoiesis (6) and B lymphocyte maturation (7). IL-11 also stimulates acute phase protein synthesis (8), regulates neuronal differentiation (9) and acts in osteoclast development (10). In vivo, IL-11 has been demonstrated to stimulate multilineage hematopoietic reconstitution and enhance recovery of intestinal epithelial cells and spermatogenesis after cytotoxic therapy (11, 12, 13).
Many of the activities of IL-11 are shared with other cytokines including IL-6, leukemia inhibitory factor (LEF), ciliary neurotrophic growth factor (CNTF) and oncostatin M (OSM) (12, 14, 15, 16, 17). These cytokines elicit their actions by binding to multi-subunit receptor complexes expressed on the surface of target cells and their overlapping biological functions may, in part, be attributable to the sharing of receptor subunits. The receptors involved in the formation of these complexes are members of the hematopoietin receptor family. Particular receptor subunits, the LIF receptor xcex1-chain and gp130, which are components of several receptors (16) are also involved. IL-6, for example, binds with low affinity to its specific xcex1-chain and with high affinity to this xcex1-chain together with two gp130 subunits (18). Similarly, IL-11 binds to the interleukin-11 receptor xcex1-chain (IL-11Rxcex1) with low affinity and to a complex of IL-11Rxcex1 and gp130 with high affinity (19, 20).
The inventors have previously cloned cDNA encoding the IL-11Rxcex1 chain and in accordance with the present invention, the inventors have now created mice in which the low affinity IL-11 receptor (IL-11Rxcex1) gene has been disrupted thereby ablating IL-11 signalling in the tissues of these mice. Surprisingly, the mice exhibited infertility. The present invention provides, therefore, a method for modulating fertility and pregnancy as well as a method for treating individuals with altered levels of IL-11, IL-11Rxcex1 or altered IL-11-receptor interaction.
Throughout this specification, unless the context requires otherwise, the word xe2x80x9ccomprisexe2x80x9d, or variations such as xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
One aspect of the present invention contemplates a method for modulating fertility in an animal, said method comprising administering to said animal an effective amount of IL-11 or a functional derivative or homologue thereof or an effective amount of an agonist or antagonist of interaction between IL-11 and IL-11Rxcex1.
In a related aspect, the present invention provides a method for modulating fertility in an animal, said method comprising modulating the levels of expression of the gene encoding IL-11 and/or its receptor.
Another aspect of the present invention contemplates a method of enhancing fertility and/or maintenance of a pregnancy in a female animal, said method comprising administering to said female animal an effective amount of IL-11 or a functional derivative or homologue thereof or an agonist thereof for a time and under conditions sufficient for a pregnancy to proceed past the early post-implantation stage.
In a related aspect, the present invention relates to a method of enhancing fertility and/or maintenance of a pregnancy in a female animal, said method comprising modulating the levels of expression of the gene encoding IL-11 and/or its receptor for a time and under conditions sufficient for a pregnancy to proceed past the early post-implantation stage.
Yet another aspect of the present invention provides a method of enhancing fertility in a male animal said method comprising administering to said male animal, an effective amount of IL-11 or a functional derivative or homologue thereof or an agonist thereof.
In a related aspect, the present invention is directed to a method of enhancing fertility in a male animal said method comprising modulating the levels of expression of the gene encoding IL-11 and/or its receptor.
Still yet another aspect of the present invention provides a method of decreasing fertility or promoting termination of a pregnancy in a female animal, said method comprising administering to said female animal an effective amount of an antagonist of IL-11 or IL-11-receptor interaction.
In a related aspect, the present invention contemplates a method of decreasing fertility or promoting termination of a pregnancy in a female animal, said method comprising modulating the levels of expression of the gene encoding IL-11 and/or its receptor.
A further aspect of the present invention contemplates a method of decreasing fertility in a male animal, said method comprising administering to said male animal an effective amount of an antagonist of IL-11 or IL-11-receptor interaction.
In a related aspect, the present invention provides a method of decreasing fertility in a male animal, said method comprising modulating the levels of expression of the gene encoding IL-11 and/or its receptor.
Another aspect of the present invention contemplates an animal model comprising a mutation in at least one allele for IL-11 and/or IL-11Rxcex1.